{"title":"GyrA 和 QnrB19 中氨基酸替代之间的相互作用:提高鼠伤寒沙门氏菌对氟喹诺酮类药物的耐药性。","authors":"Pondpan Suwanthada, Siriporn Kongsoi, Sasini Jayaweera, Mwangala Lonah Akapelwa, Jeewan Thapa, Chie Nakajima, Yasuhiko Suzuki","doi":"10.1021/acsinfecdis.4c00150","DOIUrl":null,"url":null,"abstract":"<p><p>Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal <i>Salmonella</i> (NTS), which can develop into severe and potentially life-threatening diarrhea. This study focuses on the synergistic effects of DNA gyrase mutations and plasmid-mediated quinolone resistance (PMQR) genes, specifically <i>qnrB19</i>, on fluoroquinolone (FQ) resistance in <i>Salmonella</i> Typhimurium. By utilizing recombinant mutants, GyrA<sup>S83F</sup> and GyrA<sup>D87N</sup>, and QnrB19's, we discovered a significant increase in fluoroquinolones resistance when QnrB19 is present. Specifically, ciprofloxacin and moxifloxacin's inhibitory concentrations rose 10- and 8-fold, respectively. QnrB19 was found to enhance the resistance capacity of mutant DNA gyrases, leading to high-level FQ resistance. Additionally, we observed that the ratio of QnrB19 to DNA gyrase played a critical role in determining whether QnrB19 could protect DNA gyrase against FQ inhibition. Our findings underscore the critical need to understand these resistance mechanisms, as their coexistence enables bacteria to withstand therapeutic FQ levels, posing a significant challenge to treatment efficacy.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interplay between Amino Acid Substitution in GyrA and QnrB19: Elevating Fluoroquinolone Resistance in <i>Salmonella</i> Typhimurium.\",\"authors\":\"Pondpan Suwanthada, Siriporn Kongsoi, Sasini Jayaweera, Mwangala Lonah Akapelwa, Jeewan Thapa, Chie Nakajima, Yasuhiko Suzuki\",\"doi\":\"10.1021/acsinfecdis.4c00150\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal <i>Salmonella</i> (NTS), which can develop into severe and potentially life-threatening diarrhea. This study focuses on the synergistic effects of DNA gyrase mutations and plasmid-mediated quinolone resistance (PMQR) genes, specifically <i>qnrB19</i>, on fluoroquinolone (FQ) resistance in <i>Salmonella</i> Typhimurium. By utilizing recombinant mutants, GyrA<sup>S83F</sup> and GyrA<sup>D87N</sup>, and QnrB19's, we discovered a significant increase in fluoroquinolones resistance when QnrB19 is present. Specifically, ciprofloxacin and moxifloxacin's inhibitory concentrations rose 10- and 8-fold, respectively. QnrB19 was found to enhance the resistance capacity of mutant DNA gyrases, leading to high-level FQ resistance. Additionally, we observed that the ratio of QnrB19 to DNA gyrase played a critical role in determining whether QnrB19 could protect DNA gyrase against FQ inhibition. Our findings underscore the critical need to understand these resistance mechanisms, as their coexistence enables bacteria to withstand therapeutic FQ levels, posing a significant challenge to treatment efficacy.</p>\",\"PeriodicalId\":17,\"journal\":{\"name\":\"ACS Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-08-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsinfecdis.4c00150\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsinfecdis.4c00150","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/19 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
在全球范围内,有关非伤寒沙门氏菌(NTS)对抗菌药产生耐药性的报道越来越多,这种耐药性可发展成严重的腹泻,并可能危及生命。本研究的重点是 DNA 回旋酶突变和质粒介导的喹诺酮类药物耐药性(PMQR)基因(特别是 qnrB19)对伤寒沙门氏菌氟喹诺酮类药物(FQ)耐药性的协同作用。通过利用重组突变体 GyrAS83F 和 GyrAD87N 以及 QnrB19,我们发现当 QnrB19 存在时,对氟喹诺酮类药物的耐药性会显著增加。具体来说,环丙沙星和莫西沙星的抑制浓度分别上升了 10 倍和 8 倍。研究发现,QnrB19 能增强突变 DNA 回旋酶的抗药性,从而导致高水平的 FQ 抗药性。此外,我们还观察到,QnrB19 与 DNA 回旋酶的比例在决定 QnrB19 能否保护 DNA 回旋酶免受 FQ 抑制方面起着关键作用。我们的发现强调了了解这些抗性机制的迫切需要,因为它们的共存使细菌能够承受治疗性 FQ 水平,对治疗效果构成了重大挑战。
Interplay between Amino Acid Substitution in GyrA and QnrB19: Elevating Fluoroquinolone Resistance in Salmonella Typhimurium.
Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal Salmonella (NTS), which can develop into severe and potentially life-threatening diarrhea. This study focuses on the synergistic effects of DNA gyrase mutations and plasmid-mediated quinolone resistance (PMQR) genes, specifically qnrB19, on fluoroquinolone (FQ) resistance in Salmonella Typhimurium. By utilizing recombinant mutants, GyrAS83F and GyrAD87N, and QnrB19's, we discovered a significant increase in fluoroquinolones resistance when QnrB19 is present. Specifically, ciprofloxacin and moxifloxacin's inhibitory concentrations rose 10- and 8-fold, respectively. QnrB19 was found to enhance the resistance capacity of mutant DNA gyrases, leading to high-level FQ resistance. Additionally, we observed that the ratio of QnrB19 to DNA gyrase played a critical role in determining whether QnrB19 could protect DNA gyrase against FQ inhibition. Our findings underscore the critical need to understand these resistance mechanisms, as their coexistence enables bacteria to withstand therapeutic FQ levels, posing a significant challenge to treatment efficacy.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.